study of matched unrelated donor t cell infusion for hematologic malignancies after allo-hsct

Conditions: Leukemia; Myelodysplastic Syndromes; Lymphomas; Multiple Myeloma; Other High-risk Hematological Malignancies

Summary: this is a phase i, multicenter, open-label, non-randomized study of matched unrelated donor bpx-501 t cell infusion in adult subjects with hematological malignancies presenting with recurrent disease minimal residual disease (mrd) post-allogeneic transplant.

un-manipulated donor lymphocyte infusion (dli) is used after stem cell transplantation to treat and prevent relapse, to prevent infections and to establish full donor chimerism. the addition of mature t cells which exhibit a broad repertoire of t cell immunity against viral antigens, as well as against cancer antigens, might provide a clinical benefit. however, an expected side effect of the presence of mature t cells is the potential occurrence of acute graft-versus-host disease (agvhd). the use of a suicide gene switch which would trigger the initiation of the apoptosis of the alloreactive t cells by the infusion of a drug would represent the potential optimal strategy for restoring early immunity with a built in "safety switch" against gvhd side effects. evidence has emerged that low-dose dli followed by dose escalation can achieve higher clinical response rate with lower gvhd occurrence. optimization of dli dose and schedule as well as strategies of donor t-cell manipulation may lead to the consistent ability to separate gvhd from graft-versus-tumor (gvt) activity and improve the safety of dli treatment. our strategy is to infuse escalating doses of manipulated t cells (from the same donor who provided the original hematopoietic stem cell graft) in adults and children with recurrent or minimal residual disease (mrd) hematologic malignancies post-allogeneic transplant to accelerate immune reconstitution thus improving graft versus leukemic effect while reducing the severity of gvhd.

Eligibility criteria:
inclusion criteria: * subjects aged ≥ 18 yrs and ≤ 65 yrs; * clinical diagnosis of one of the following hematological malignancies: * leukemia * myelodysplastic syndromes * lymphomas * multiple myeloma * other high-risk hematological malignancy eligible for stem cell transplantation per institutional standard; * recurrent disease that presents ≥100 days after, or minimal residual disease (mrd) that presents ≥ 30 days following a hematopoietic stem cell transplant (hsct) using a matched unrelated donor located through the national marrow donor program (nmdp); * life expectancy \>10 weeks; * signed donor and patient/guardian informed consent; * a 8/8 genotypic identical match as determined by high resolution typing for the following genetic loci: human leukocyte antigen (hla)-a, hla-b, hla-c and hla-drb1; * performance status: karnofsky score \> 50%; * subjects with adequate organ function as measured by: * bone marrow: * \> 25% donor t-cell chimerism post-transplant * absolute neutrophil count (anc) \>1 x 109/l * cardiac: left ventricular ejection fraction (lvef) at rest ≥ 45% * pulmonary: forced expiratory volume (fev) 1, forced vital capacity (fvc), diffusion capacity of lunch for carbon monoxide (dlco) ≥ 50% predicted (corrected for hemoglobin) * hepatic: direct bilirubin ≤ 3x upper limit of normal (uln), or aspartate aminotransferase (ast)/alanine aminotransferase (alt) ≤ 5x uln * renal: creatinine ≤ 2x of uln for age. exclusion criteria: * ≥ grade ii acute gvhd or chronic extensive gvhd due to a previous allograft at the time of screening; * active central nervous system (cns) involvement with malignant cells (≤ 2 months prior to consenting); * current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings); the principal investigator is the final arbiter of this criterion; * positive hiv serology or viral rna; * pregnancy (positive serum β human chorionic gonadotropin \[hcg\] test) or breast-feeding; * fertile men or women unwilling to use effective forms of birth control or abstinence for one year after transplantation; * bovine product allergy.

Keywords: bpx-501 rimiducid ap1903 hematological malignancies hematologic diseases leukemias and myelodysplastic syndromes lymphomas multiple myeloma